Análisis prospectivo del impacto de mutaciones en genes implicados en la reparación del daño del ADN, en la respuesta a radium-223 en cáncer de próstata metastásico resistente a castración

Resumo

BACKGROUND: Radium-223 is an a-emitting radiopharmaceutical targeted at bonetissue, inducing double-strand DNA breaks (DSBs). These DSBs are precisely repairedthrough the homologous recombination (HRR) pathway. In a significant proportion ofmetastatic castration-resistant prostate cancer (mCRPC) patients harboring pathogenicgermline mutations in HRR genes (gHRR+), this pathway is altered. We hypothesized thatgHRR+ patients are more likely to respond to radium-223 than those without thesealterations (gHRR-). METHODS: We conducted a prospective observational cohort study involving mCRPC patients treated with standard radium-223 therapy. Germline mutations in HRR geneswere analyzed using a multi-gene panel. The primary endpoint was alkaline phosphatase(ALP) response. We also assessed PSA response at 12 weeks, time to PSA progression(TTPP), clinical and radiological progression-free survival (cPFS and rPFS), overall survival(OS), and cancer-specific survival (CSS) following radium-223 administration. The medianfollow-up duration was 31 months. RESULTS: The study included 169 mCRPC patients. Median age at inclusion was 73 years(range 45-90). ECOG functional status <1 was recorded in 85% of patients. The mediannumber of prior therapy lines for mCRPC was 2 (range 0-4), with at least one taxaneincluded in 63% of patients. Most patients (59.2%) received :25 cycles of radium-223.A pathogenic gHRR mutation was identified in 15 (8.8%) patients (5 BRCA2, 4 ATM, 1BRCA1, 1 CHEK2, 1 BRCA1 +CHEK2, 1 BRIP1, 1 NBN, 1 BLM). A :230% decrease in ALP at 12weeks was observed in 71.4% of gHRR+ patients compared to 39.5% of gHRR- patients(p=0.022). No differences were observed in the reduction of PSA :250% at 12 weeks ortime to PSA progression (TTPP) (2.8 versus 3.0 months, p=0.721). The gBRCA2 and gATMmutations (n=9) were significantly associated with improved overall survival (OS), with amedian OS of 25.2 versus 12.0 months in non-carriers (HR 0.44, 95% CI 0.21-0.96). The median OS for radium-223 was 6.8 months in gHRR+ patients and 11.5 months in gHRR patients(p = 0.078). Cancer-specific survival (CSS) was significantly prolonged in patients with gATM mutations compared to non-carriers (28.8 versus 15.9 months, p = 0.017). CONCLUSIONS: patients with gHRR mutations were associated with a better ALP responseand a trend towards a more prolonged overall survival (OS), suggesting a benefit ofradium-223 in sorne gHRR+ patients, particularly those with gBRCA2 and gATMmutations.